Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud, Thiruvananthapuram 695014, Kerala, India; PhD Program, Manipal Academy of Higher Education (MAHE), Madhav Nagar, Manipal, Karnataka 576104, India.
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud, Thiruvananthapuram 695014, Kerala, India.
Int J Biol Macromol. 2024 Apr;264(Pt 1):130151. doi: 10.1016/j.ijbiomac.2024.130151. Epub 2024 Feb 24.
Reactivation of telomerase is a hallmark of cancer and the majority of cancers over-express telomerase. Telomerase-dependent telomere length maintenance confers immortality to cancer cells. However, telomere length-independent cell survival functions of telomerase also play a critical role in tumorigenesis. Multiple telomerase inhibitors have been developed as therapeutics and include anti-sense oligonucleotides, telomerase RNA component targeting agents, chemical inhibitors of telomerase, small molecule inhibitors of hTERT, and telomerase vaccine. In general, telomerase inhibitors affect cell proliferation and survival of cells depending on the telomere length reduction, culminating in replicative senescence or cell death by crisis. However, most telomerase inhibitors kill cancer cells prior to significant reduction in telomere length, suggesting telomere length independent role of telomerase in early telomere dysfunction-dependent cell death.
In this study, we explored the mechanism of cell death induced by three prominent telomerase inhibitors utilizing a series of genetically encoded sensor cells including redox and DNA damage sensor cells.
We report that telomerase inhibitors induce early cell cycle inhibition, followed by redox alterations at cytosol and mitochondria. Massive mitochondrial oxidation and DNA damage induce classical cell death involving mitochondrial transmembrane potential loss and mitochondrial permeabilization. Real-time imaging of the progression of mitochondrial oxidation revealed that treated cells undergo a biphasic mitochondrial redox alteration during telomerase inhibition, emphasizing the potential role of telomerase in the redox regulation at mitochondria. Additionally, silencing of hTERT confirmed its predominant role in maintaining mitochondrial redox homeostasis. Interestingly, the study also demonstrated that anti-apoptotic Bcl-2 family proteins still confer protection against cell death induced by telomerase inhibitors.
The study demonstrates that redox alterations and DNA damage contribute to early cell death by telomerase inhibitors and anti-apoptotic Bcl-2 family proteins confer protection from cell death by their ability to safeguard mitochondria from oxidation damage.
端粒酶的重新激活是癌症的一个标志，大多数癌症过度表达端粒酶。端粒酶依赖性端粒长度维持赋予癌细胞永生。然而，端粒酶的端粒长度非依赖性细胞存活功能在肿瘤发生中也起着关键作用。已经开发出多种端粒酶抑制剂作为治疗剂，包括反义寡核苷酸、端粒酶 RNA 成分靶向剂、端粒酶的化学抑制剂、小分子 hTERT 抑制剂和端粒酶疫苗。一般来说，端粒酶抑制剂根据端粒长度的减少影响细胞增殖和细胞存活，最终导致复制性衰老或危机导致的细胞死亡。然而，大多数端粒酶抑制剂在端粒长度显著减少之前杀死癌细胞，这表明端粒酶在早期端粒功能障碍依赖性细胞死亡中具有端粒长度非依赖性作用。
在这项研究中，我们利用一系列遗传编码的传感器细胞，包括氧化还原和 DNA 损伤传感器细胞，探索了三种主要的端粒酶抑制剂诱导细胞死亡的机制。
我们报告称，端粒酶抑制剂诱导早期细胞周期抑制，随后细胞质和线粒体发生氧化还原改变。大量的线粒体氧化和 DNA 损伤诱导涉及线粒体跨膜电位丧失和线粒体通透性的经典细胞死亡。线粒体氧化进展的实时成像显示，在端粒酶抑制过程中，处理后的细胞经历了两次线粒体氧化还原改变，强调了端粒酶在调节线粒体氧化还原中的潜在作用。此外，hTERT 的沉默证实了其在维持线粒体氧化还原稳态中的主要作用。有趣的是，该研究还表明，抗凋亡 Bcl-2 家族蛋白仍然可以通过保护线粒体免受氧化损伤来对抗端粒酶抑制剂诱导的细胞死亡。
该研究表明，氧化还原改变和 DNA 损伤导致端粒酶抑制剂诱导的早期细胞死亡，而抗凋亡 Bcl-2 家族蛋白通过保护线粒体免受氧化损伤来对抗细胞死亡。
